This invention relates to peptides which are presented by MHC molecules, leading to recognition by cytolytic T cells. More specifically, it relates to peptides which bind to HLA-B35 molecules, and are nonamers.
The process by which the mammalian immune system recognizes and reacts to foreign or alien materials is a complex one. An important facet of the system is the T cell response. This response requires that T cells recognize and interact with complexes of cell surface molecules, referred to as human leukocyte antigens (xe2x80x9cHLAxe2x80x9d), or major histocompatibility complexes (xe2x80x9cMHCsxe2x80x9d), and peptides. The peptides are derived from larger molecules which are processed by the cells which also present the HLA/MHC molecule. See in this regard Male et al., Advanced Immunology (J. P. Lipincott Company, 1987), especially chapters 6-10. The interaction of T cell and complexes of HLA/peptide is restricted, requiring a T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell is not present, there is no T cell response even if its partner complex is present. Similarly, there is no response if the specific complex is absent, but the T cell is present. This mechanism is involved in the immune system""s response to foreign materials, in autoimmune pathologies, and in responses to cellular abnormalities. Much work has focused on the mechanisms by which proteins are processed into the HLA binding peptides. See, in this regard, Barinaga, Science 257:880 (1992); Fremont et al., Science 257:919(1992); Matsumura et al., Science 257:927 (1992); Latron et al., Science 257:964 (1992).
The mechanism by which T cells recognize cellular abnormalities has also been implicated in cancer. For example, in PCT application PCT/US92/04354, filed May 22, 1992, published on Nov. 26, 1992, and incorporated by reference, a family of genes is disclosed, which are processed into peptides which, in turn, are expressed on cell surfaces, which can lead to lysis of the tumor cells by specific CTLs. The genes are said to code for xe2x80x9ctumor rejection antigen precursorsxe2x80x9d or xe2x80x9cTRAPxe2x80x9d molecules, and the peptides derived therefrom are referred to as xe2x80x9ctumor rejection antigensxe2x80x9d or xe2x80x9cTRAsxe2x80x9d. See Traversari et al., Immunogentics 35:145 (1992); van der Bruggen et al., Science 254:1643 (1991), both of which are incorporated by reference for further information on this family of genes.
In U.S. Pat. No. 5,405,940, the disclosure of which is incorporated by reference, nonapeptides are taught which bind to the HLA-A1 molecule. The patent teaches that, given the known specificity of particular peptides for particular HLA molecules, one should expect a particular peptide to preferentially bind one particular HLA molecule, but not others. This is important, because different individuals possess different HLA phenotypes. As a result, while identification of a particular peptide as being a partner for a specific HLA molecule or class of HLA molecules has diagnostic and therapeutic ramifications, these are only relevant for individuals with that particular HLA phenotype. There is a need for further work in the area, because many cellular abnormalities are not restricted to one particular HLA phenotype, and targeted therapy requires some knowledge of the phenotype of the abnormal cells at issue.
The enzyme tyrosinase catalyzes the reaction converting tyrosine to dehydroxyphenylalanine or xe2x80x9cDOPAxe2x80x9d and appears to be expressed selectively in melanocytes (Muller et al., EMBO J 7:2715 (1988)). An early report of cDNA for the human enzyme is found in Kwon, U.S. Pat. No. 4, 898,814. A later report by Bouchard et al., J. Exp. Med. 169:2029 (1989) presents a slightly different sequence. A great deal of effort has gone into identifying inhibitors for this enzyme, as it has been implicated in pigmentation diseases. Some examples of this literature include Jinbow, WO9116302; Mishima et al., U.S. Pat. No. 5,077,059, and Nazzaropor, U.S. Pat. No. 4,818,768. The artisan will be familiar with other references which teach similar materials.
Various U.S. Patent Applications incorporated by reference herein, teach that tyrosinase may be treated in a manner similar to a foreign antigen or a TRAP moleculexe2x80x94i.e., it was found that in certain cellular abnormalities, such as melanoma, tyrosinase is processed and a peptide derived therefrom forms a complex with HLA molecules on certain abnormal cells. These complexes were found to be recognized by cytolytic T cells (xe2x80x9cCTLsxe2x80x9d), which then lyse the presenting cells.
For example, allowed patent application Ser. No. 08/583,238, filed Jan. 5, 1996, now U.S. Pat. No. 5,843,688, teaches peptides which are derived from tyrosinase, and which complex to HLA-A2 and HLA-B44 molecules. Additional information on peptides derived from tyrosinase which are presented by HLA molecules may be found in U.S. Pat. No. 5,487,974, and patent applications Ser. No. 08/203,054, filed Feb. 28, 1994, Ser. No. 08/081,673, filed Jun. 23, 1993 and Ser. No. 07/994,928, filed Dec. 22, 1992, and now abandoned. All of these references are incorporated by reference.
It is known that HLA-B35 molecules present peptides, with the resulting complexes being recognized by CTLs. See, in this regard, allowed U.S. patent application Ser. No. 08/718,964, filed Sep. 26, 1996, now U.S. Pat. No. 5,932,694 and incorporated by reference. Other information on presentation by HLA-B35 molecules may be found in, e.g., Rammensee, et al., Immunogenetics 41:171 (1995), page 207 in particular, incorporated by reference. Also see Mason, et al., Tissue Antigens 51:417-465 (1998) incorporated by reference. Page 458 lists the amino acid sequences for the known HLA-B35 alleles, and shows that there is a great deal of identity there between.
New peptides have been identified which bind to HLA-B35 molecules, and are then recognized by CTLs. It is these peptides, and their use, which constitute the invention.
While derived from tyrosinase, the peptides of the invention need not be derived therefrom, as will be clear to the skilled artisan, and which will be seen from the disclosure which follows.